全文获取类型
收费全文 | 1500篇 |
免费 | 78篇 |
国内免费 | 63篇 |
出版年
2024年 | 5篇 |
2023年 | 29篇 |
2022年 | 29篇 |
2021年 | 64篇 |
2020年 | 64篇 |
2019年 | 85篇 |
2018年 | 76篇 |
2017年 | 50篇 |
2016年 | 55篇 |
2015年 | 49篇 |
2014年 | 96篇 |
2013年 | 127篇 |
2012年 | 48篇 |
2011年 | 71篇 |
2010年 | 46篇 |
2009年 | 67篇 |
2008年 | 65篇 |
2007年 | 77篇 |
2006年 | 61篇 |
2005年 | 56篇 |
2004年 | 57篇 |
2003年 | 43篇 |
2002年 | 37篇 |
2001年 | 17篇 |
2000年 | 23篇 |
1999年 | 26篇 |
1998年 | 16篇 |
1997年 | 26篇 |
1996年 | 12篇 |
1995年 | 20篇 |
1994年 | 11篇 |
1993年 | 18篇 |
1992年 | 19篇 |
1991年 | 8篇 |
1990年 | 5篇 |
1989年 | 14篇 |
1988年 | 3篇 |
1987年 | 4篇 |
1986年 | 14篇 |
1985年 | 7篇 |
1984年 | 11篇 |
1983年 | 5篇 |
1982年 | 5篇 |
1981年 | 6篇 |
1980年 | 4篇 |
1979年 | 2篇 |
1977年 | 1篇 |
1976年 | 3篇 |
1974年 | 2篇 |
1972年 | 1篇 |
排序方式: 共有1641条查询结果,搜索用时 125 毫秒
31.
Interactions of hemin, antimalarial drugs and hemin-antimalarial complexes with phospholipid monolayers 总被引:1,自引:0,他引:1
Hemin, antimalarial drugs and complexes formed between them, have demonstrable effects on biological membranes. Using the phospholipid monolayer model, we show that hemin intercalates into the membrane and increases its surface pressure, depending on the lipid composition and the initial surface pressure: negative surface charges and particularly looser compaction of the phospholipids reduce the effect of hemin. With increasing surface pressure hemin tends to intercalate as a monomer, and the half-saturation concentration of its effect increases exponentially. The antimalarial monovalent drugs quinine and mefloquine, but not chloroquine, also penetrate into the membrane and expand it. All three drugs markedly increase the effect of hemin, but chloroquine reduces the effect in monolayers composed of unsaturated phospholipids. The drugs' effect is mostly due to an increase in the maximal surface pressure and suggests a complexation of hemin and drug within the membrane phase. Preformed hemin-drug complexes decrease the half-saturation concentration of the effect and suggest that the complexes adsorb to the membrane, releasing the hemin through an apolar continuum into the phospholipid phase. The implications of the results to the membrane toxicity mechanism proposed for the molecular mode of action of antimalarial drugs are discussed. 相似文献
32.
Michinori Ichikawa Masashi Urayama Gen Matsumoto 《The Journal of membrane biology》1991,120(3):211-222
Summary The effects of calmodulin (CaM) antagonists (W-7, W-5, trifluoperazine, chlorpromazine, quinacrine, diazepam, propericyazine and carmidazolium) on the sodium and potassium channels were studied on the intracellularly perfused and voltage-clamped giant axon of the squid. It was found that the drugs are more potent blockers of the sodium current than of the potassium current. The drugs also reduce the sodium gating current. The blockage of the sodium and gating current can be explained by assuming that the drugs interact with the sodium gating subunit in one of its closed states. The site of action is probably the intracellular surface of the axolemma where presumably a Ca2+-calmodulin complex can be formed. 相似文献
33.
Kathleen R. Melia Kurt Rasmussen Rose Z. Terwilliger John W. Haycock† Eric J. Nestler Ronald S. Duman 《Journal of neurochemistry》1992,58(2):494-502
Recent studies have demonstrated that chronic stress increases the firing rate and expression of tyrosine hydroxylase (TH) in neurons of the locus coeruleus (LC), the major noradrenergic nucleus in brain. The present study was undertaken to examine the influence of chronic stress and other treatments known to influence the activity of LC neurons on the cyclic AMP (cAMP) second messenger system in these neurons. Chronic (5 days) cold exposure significantly increased levels of TH immunoreactivity in the LC, as previously reported, but not in substantia nigra (SN) or ventral tegmentum (VT), two dopaminergic nuclei studied for comparison. Chronic cold exposure increased levels of cAMP-dependent protein kinase activity in soluble, but not particulate, fractions of the LC, and increased basal and GTP- and forskolin-stimulated adenylate cyclase activity in this brain region. In contrast, levels of the protein kinase and adenylate cyclase in VT, SN, and frontal cortex were not significantly influenced by cold exposure. To study further the relationship between regulation of LC firing rate, TH expression, and the cAMP system in the LC, other treatments known to influence TH were examined. Reserpine treatment, shown previously to increase levels of TH, was found to increase both LC firing rate and levels of soluble cAMP-dependent protein kinase activity in the LC. 6-Hydroxydopamine, shown previously to increase levels of TH and firing rate of LC neurons, also increased soluble levels of protein kinase activity. Other treatments known to either increase (adrenalectomy) or decrease (chronic imipramine) levels of TH in the LC were also found to increase or decrease, respectively, levels of cAMP-dependent protein kinase activity in this brain region.(ABSTRACT TRUNCATED AT 250 WORDS) 相似文献
34.
Summary Elementary Na+ currents were recorded in cell attached patches from short-time cultured neonatal cardiocytes in order to test the hypothesis whether the open state of DPI-modified, noninactivating cardiac Na+ channels is basically sensitive to blocking drug molecules such as antiarrhythmics.Lidocaine (300 mol/liter) effectively reduced the open probability of cardiac Na+ channels and, at a stimulation rate of 1 Hz, depressed the reconstructed macroscopic peak I
Na to 40+ 3.5% of the predrug value. The same drug concentration failed to influence DPI-modified Na+ channels. Their open state proved almost insensitive to lidocaine. open decreased only slightly to 85 ±2%. Still more importantly, the number of transitions between the conducting and a nonconducting configuration did not increase. At –40 mV, lidocaine may interfere with the open state with an association rate constant of 1.3×105 mol–1sec–1 which is about two orders of magnitude smaller than the rate constant obtained with propafenone or prajmalium. Moreover, propafenone (10–20 mol/liter) or prajmalium (30 mol/liter) led to a tremendous increase in the number of transitions between the open and a nonconducting configuration. Lidocaine also failed to evoke a fast flicker blockade with reaction kinetics in the microsecond range.It is concluded that DPI-modified cardiac Na+ channels discriminate between lidocaine and other antiarrhythmic drugs. As a tentative explanation, this might be indicative for multiple binding sites for those drugs in cardiac Na+ channels.This work was supported by a grant from the Deutsche Forschungs-gemeinschagt (Ko 778/2–3), Bonn. 相似文献
35.
Alterations of Phospholipid Metabolism in Rat Cerebral Cortex Mince Induced by Cationic Amphiphilic Drugs 总被引:3,自引:3,他引:0
Abstract Cationic amphiphilic drugs (CADs) of varied clinical use were screened to determine their capacity to alter the pattern of labeling with 32 Pj of cerebral cortex mince phospholipids. The altered phospholipid labeling patterns were qualitatively similar, the prominent features being reduced incorporation into phosphatidylcholine and increased incorporation into phosphatidic acid. Relative potencies were: (±)-propranolol > chlorpromazine = 4,4'-bis(diethylaminoethoxy) α,β -diethyldiphenylethane > desipramine > di-bucaine > pimozide > oxymetazoline = fenfluramine = haloperidol = chloroquine > amphetamine = no drug added. Propranolol was used to study the action of CADs further. Its effect was time- and dose-dependent, but in contrast with pineal gland, no label appeared in phosphatidyl-CMP (CDP-diacylglycerol), nor did dialysis of the mince to reduce diffusible substrates or exogenous addition of substrates cause appearance of liponucleotide. Thus lack of diffusible precursors is not responsible for CAD effects in vitro. Pulse-chase experiments with 32 P1 and [2-3 H]glycerol suggested that inhibition of phosphatidate phosphohydrolase may be partly responsible for the observed alterations in phospholipid labeling in the presence of CADs. 相似文献
36.
Corrado Barghigiani Giuliano Colombetti Francesco Lenci Rosalba Banchetti Maria Pia Bizzaro 《Archives of microbiology》1979,120(3):239-245
We have investigated the effect of some metabolic drugs, 3-(3,4-dichlorophenyl)-1,1-dimethylurea (DCMU), 2,4-dinitrophenol (DNP), sodium azide (NaN3), on the photobehavior of single cells of Euglena gracilis, in order to clarify the relevance of different metabolic pathways in the process of photoperception and sensory transduction in this alga. The results obtained show that the photophobic response of Euglena is not affected by the action of these drugs. This suggests that neither the photosynthetic process nor oxidative phosphorylation play a significant role in the phenomenon of photosensory transduction in Euglena.List of Abbreviations DNP
2,4-dinitrophenol
- DCMU
3-(3,4-dichlorophenyl)-1,1-dimethylurea
- PSI
Photosystem I
- PSII
Photosystem II 相似文献
37.
Cercariae of Schistosoma mansoni were treated with undecenyl-pseudothiourea. After centrifugation, they agglutinated into a mass. Resuspended in water, they remained immobilized. When injected sub-cutaneously into mice, they produced bisexual infections. The immobilizing drug effect, together with a reduced worm recovery rate, are time and concentration dependent. The cercariae become avirulent (99.8%) only when the flame cell is affected. Immobilizing and “cercaricidal” effects are not necessarily related properties; the latter can be determined only by in vivo tests of infectivity. No protection against reinfection was noticed in mice injected with immobilized cercariae of reduced virulence. The immobilized cercariae produced infections with a 0.7% worm recovery rate by percutaneous exposure, compared to 2.2% by subcutaneous injection. Normal cercariae produced infections with average recovery rates of 11.1% subcutaneously and 45% percutaneously. 相似文献
38.
The concept of additivity of drug combinations is widely accepted in pharmacology and toxicology. Up to now, no general statistical methods to test that property are available. The present paper gives a mathematical formulation of additivity, a method to fit dose response surfaces under additivity assumption and a statistical test. 相似文献
39.
40.
微生态药物在许多复杂性和慢性疾病中显示出极大的潜力,逐渐成为国际制药行业的新趋势。基于科睿唯安旗下的Cortellis数据库,采用定量分析和专家智慧相结合的方法,从总体研发现状、主要国家/地区、主要适应症、重点企业研发管线、重点在研药物、商业化交易多个维度展现全球微生态药物的研发和商业化全景。分析结果显示:全球共有142个在研微生态药物,其中49个药物处于临床阶段。美国在微生态药物研发和商业化方面遥遥领先,其数量占在研药物总量的70%。在研药物的适应症主要集中于炎症性肠病、艰难梭菌感染、溃疡性结肠炎等肠道感染性疾病。4D pharma公司的在研药物数量最多,微生态药物重点研发企业均建立起核心技术平台。处于临床3期的微生态药物共有7个,全球微生态药物商业化交易共有303起,最大的交易金额是27.8亿美元。未来,微生态药物有望在更难被人类征服的肿瘤和神经系统疾病方面取得突破性进展。 相似文献